Principles of dimer-specific gene regulation revealed by a comprehensive characterization of NF-κB family DNA binding

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Abstract

The unique DNA-binding properties of distinct NF-κB dimers are known to influence the selective regulation of NF-κB target genes. To gain a stronger appreciation for these dimer-specific differences, we have combined protein-binding microarrays (PBM) and surface plasmon resonance (SPR) to evaluate DNA sites recognized by eight different NF-κB dimers. We observed three distinct binding-specificity classes and provide insight into mechanisms by which dimers might regulate distinct sets of genes. We identified many new non-traditional κB site sequences and highlight an under-appreciated plasticity of NF-κB dimers in recognizing κB sites with a single consensus half-site. This study provides a database that will be of broad utility in efforts to identify NF-κB target sites and uncover gene regulatory circuitry.

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Most cited references 37

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Variation in transcription factor binding among humans.

Maya Kasowski, Fabian Grubert, Christopher Heffelfinger … (2010)

Differences in gene expression may play a major role in speciation and phenotypic diversity. We examined genome-wide differences in transcription factor (TF) binding in several humans and a single chimpanzee by using chromatin immunoprecipitation followed by sequencing. The binding sites of RNA polymerase II (PolII) and a key regulator of immune responses, nuclear factor kappaB (p65), were mapped in 10 lymphoblastoid cell lines, and 25 and 7.5% of the respective binding regions were found to differ between individuals. Binding differences were frequently associated with single-nucleotide polymorphisms and genomic structural variants, and these differences were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, comparing PolII binding between humans and chimpanzee suggests extensive divergence in TF binding. Our results indicate that many differences in individuals and species occur at the level of TF binding, and they provide insight into the genetic events responsible for these differences.

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Series introduction: the transcription factor NF-kappaB and human disease.

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Transcriptional regulation via the NF-kappaB signaling module.

A Hoffmann, G Natoli, G Ghosh (2006)

Stimulus-induced nuclear factor-kappaB (NF-kappaB) activity, the central mediator of inflammatory responses and immune function, comprises a family of dimeric transcription factors that regulate diverse gene expression programs consisting of hundreds of genes. A family of inhibitor of kappaB (IkappaB) proteins controls NF-kappaB DNA-binding activity and nuclear localization. IkappaB protein metabolism is intricately regulated through stimulus-induced degradation and feedback re-synthesis, which allows for dynamic control of NF-kappaB activity. This network of interactions has been termed the NF-kappaB signaling module. Here, we summarize the current understanding of the molecular structures and biochemical mechanisms that determine NF-kappaB dimer formation and the signal-processing characteristics of the signaling module. We identify NF-kappaB-kappaB site interaction specificities and dynamic control of NF-kappaB activity as mechanisms that generate specificity in transcriptional regulation. We discuss examples of gene regulation that illustrate how these mechanisms may interface with other transcription regulators and promoter-associated events, and how these mechanisms suggest regulatory principles for NF-kappaB-mediated gene activation.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Journal ID (iso-abbrev): Nat. Immunol.

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 17 October 2011

Publication date (Electronic): 20 November 2011

Publication date PMC-release: 01 July 2012

Volume: 13

Issue: 1

Pages: 95-102

Affiliations

[1 ]Division of Genetics, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

[2 ]Molecular Biology Institute and Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA

[3 ]Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, UK

[4 ]Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA

[5 ]Kennedy Institute of Rheumatology, Imperial College, London, UK

[6 ]Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

Author notes

[7]

These authors contributed equally to this work.

[* ]Correspondence should be addressed to M.L.B. ( mlbulyk@ 123456receptor.med.harvard.edu ).

Author Contributions

T.S. designed and performed PBM experiments, and performed ChIP data analysis. T.S. and B.A. performed PBM data analyses. A.B.C. and K.J.W. made murine protein samples. A.B.C. performed SPR experiments. A.T., D.W., J.R. and I.A.U. provided human protein samples. The manuscript was written by T.S., A.B.C., S.T.S. and M.L.B.

Article

Manuscript ID: UKMS36777

DOI: 10.1038/ni.2151

PMC ID: 3242931

PubMed ID: 22101729

SO-VID: 661c6572-138a-45fb-aa7d-004779cc2824

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History

Funding

Funded by: Wellcome Trust :

Award ID: 084818 || WT

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